Obesity is strongly associated with dysregulation of lipid and glucose metabolism, and in turn with increased risk of cardiovascular morbidity and mortality [1]. This increased risk is believed to stem, at least in part, from a level of tonic, subclinical inflammation higher than that seen in normal-weight subjects. Understanding obesity and its attendant metabolic complications has never been more important, given that up to 32% of Americans suffer from this condition [2]. The first specific aim of our study is to determine the effect of prolonged, therapeutic dose anti-inflammatory therapy with a TNF-alpha (TNF-a) antagonist, etanercept, on markers of cardiovascular risk in patients with obesity and metabolic dysregulation. Monitored endpoints will include anthropometric measurements, levels of inflammatory cytokines, lipid levels, glucose levels in response to oral glucose tolerance testing, flow-mediated vasodilation on peripheral arterial tonometry, and visceral and subcutaneous fat quantification on abdominal CT scanning. The second aim is to understand the effect of such therapy on adipose tissue expression of TNF-a, soluble TNF-a receptors (sTNFR's), endothelial cell leukocyte adhesion markers, chemokines, macrophage polarization markers, endoplasmic reticulum (ER) stress markers, and adipocytokines, as measured in biopsied subcutaneous fat samples from these patients. Forty patients with obesity and metabolic dysregulation will be randomized to receive etanercept or identical placebo for six months. Our hypothesis is that prolonged, therapeutic dose etanercept treatment will decrease both systemic and local inflammation in this patient population, and in so doing may attenuate cardiovascular risk and improve insulin sensitivity. This research will benefit the public health in two important ways. First, it will help to elucidate the pathogenesis of cardiovascular complications associated with obesity, a rampant condition with profoundly negative health consequences. A better understanding of this condition and its complications could in turn lead to effective therapeutic interventions. Second, it will help explain the link between obesity, inflammation, endothelial dysfunction, and insulin resistance. Such information will have treatment implications for a broad spectrum of clinical and subclinical inflammatory conditions in which cardiovascular and metabolic risk is increased.